EP0021688B1 - 7-(Thiazolylpropionamido)-cephalosporine, ihre Herstellung und sie enthaltende pharmazeutische Zusammensetzungen - Google Patents

7-(Thiazolylpropionamido)-cephalosporine, ihre Herstellung und sie enthaltende pharmazeutische Zusammensetzungen Download PDF

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Publication number
EP0021688B1
EP0021688B1 EP80301917A EP80301917A EP0021688B1 EP 0021688 B1 EP0021688 B1 EP 0021688B1 EP 80301917 A EP80301917 A EP 80301917A EP 80301917 A EP80301917 A EP 80301917A EP 0021688 B1 EP0021688 B1 EP 0021688B1
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Prior art keywords
group
carboxylic acid
cephem
acid
protected
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EP80301917A
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French (fr)
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EP0021688A1 (de
Inventor
Masaru Iwanami
Akio Koda
Yukiyasu Murakami
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Yamanouchi Pharmaceutical Co Ltd
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Yamanouchi Pharmaceutical Co Ltd
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Priority claimed from JP7159579A external-priority patent/JPS55164690A/ja
Priority claimed from JP3001980A external-priority patent/JPS56127388A/ja
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/587—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with aliphatic hydrocarbon radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms, said aliphatic radicals being substituted in the alpha-position to the ring by a hetero atom, e.g. with m >= 0, Z being a singly or a doubly bound hetero atom
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • This invention relates to cephalosporins wherein a propionamido group having a free or substituted hydroxy group at the 3-position and a thiazolyl group at the 2-position is linked to the 7- position of the cephalosporin and to their production.
  • cephalosporin derivatives having as a side chain acylamino group at the 7-position a propionamido group in which the 3-position is substituted with a hydroxy group and the 2-position is substituted with a heterocyclic group are disclosed in Japanese Patent Applications (Open for Public Inspection) Nos. 101,338/'78, 16,495/'79 and 36,286/'79.
  • cephalosporins show some antibacterial activity against Bacillus subtilis which is a gram positive bacterium, but little against species such as Shigella sonnei and Proteus mirabilis.
  • the present invention provides cephalosporin derivatives represented by following general formula I wherein
  • French Specification No. 2,343,747 discloses various antibacterial cephalosporin derivatives including, for example, 3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-7-(2-(2-amino-1,3-thiazol-4-yl)glyoxylamido]-3-cephem-4-carboxylic acid, but antibacterial activity is demonstrated only against E. coli.
  • 2,356,654 also discloses various antibacterial cephalosporin derivatives, including for example 2-methyl-7-[2-hydroxy-2-(2-aminothiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid, but these differ from the compounds of the present invention in being substituted at the 2-position rather than the 3-position of the cephalosporanic ring.
  • Antibacterial cephalosporin compounds disclosed in European Specification No. 0,001,125 also differ structurally from those of the present invention, e.g. in the nature of the substituent at the 3-position and of the amido group at the 7-position.
  • a protective group for the amino group one conventionally used in the fields of cephalosporin and peptide chemistry is preferably employed, and examples of such protective groups are the trityl, trimethylsilyl, formyl, propionyl, methoxyacetyl, benzyloxy, carbonyl, t-butoxycarbonyl and phthaloyl groups.
  • a protective group for the carboxy i.e.
  • carboxylic acid) group one conventionally used in the above-mentioned fields is preferably employed, examples being the methyl, trimethylsilyl, 13-methylsulfonylethyl, phenacyl, p-methoxybenzyl, nitrobenzyl, benzyl, benzhydryl, t-butyl, phthalidyl and pivaloyloxymethyl groups.
  • the protective groups used are preferably those which, when the compound is administered to a living body, accelerate absorption of the compound and are easily released in the body.
  • Examples of such protective groups are acetyl and carboxy groups for the amino group, and phthalidyl and pivaloyloxymethyl groups for the carboxylic acid group.
  • cephalosporin compounds of this invention show antibacterial activity against various pathogens, particularly such as Shigella sonnei and Proteus mirabilis. They may be made up in a carrier to provide pharmaceutical compositions.
  • the antibacterial activities of compounds of formula I are shown in the following Table, in comparison with known compounds having similar structures.
  • cephalosporin compounds of formula can be administered orally or parenterally, in their free form or in the form of salts, for the treatment of diseases of human beings and animals.
  • the dosage of the cephalosporin compounds depends inter alia on the condition, weight, and age of the patient but for an adult human is usually a total of 250-3000 mg per day, administered in 3 to 4 doses spaced over the day.
  • the forms of the compounds of the invention suitable for administration include injections, tablets, capsules, syrups, etc., and can be prepared conventionally using excipients, preservatives, stabilisers, etc., commonly used in medicament formulations.
  • a cephalosporin compound of formula I can be prepared by reacting a 7j3-aminocephalosporin derivative shown by general formula II or a reactive derivative thereof in which the amino group is substituted, wherein R 2 has the same significance as above and the carboxy group may be protected by a conventional protective group, with (b) a thiazolylpropionic acid derivative represented by the general formula or a reactive derivative thereof in which the carboxylic acid group is substituted, wherein R has the same significance as above and the hydroxy group when R is hydrogen and/or the amino group may be protected by a conventional protective group, if desired treating the product to convert any protected group to the free group, and optionally converting the reaction product to a salt thereof.
  • the carboxy group at the 4-position may be in the form of its sodium, potassium or triethylamine, etc. salt.
  • the reaction of the compound of formula II and the compound of formula III is suitably performed in a solvent with cooling or at room temperature. Any solvent which does not adversely influence the reaction may be used; suitably one or more of tetrahydrofuran, acetone, chloroform, methanol, ethanol, methylene chloride, ethylene chloride, acetonitrile, ethyl acetate, ethyl formate, and dimethylformamide is used.
  • Suitable reactive derivatives of the formula III compounds in which the carboxy group is substituted include acid halides, mixed acid anhydrides, active esters, active amides, acid anhydrides, acid azides, etc.
  • the formula III compound is an acid halide such as an acid chloride or is an acid anhydride or mixed acid anhydride
  • a base is preferred to perform the reaction in the presence of a base.
  • suitable bases are organic bases such as triethylamine, pyridine, dimethylaniline, etc., and inorganic bases such as an alkali carbonate, an alkali hydrogencarbonate, etc.
  • the hydroxy group may, if necessary, be protected by a protective group conventionally used in the field of peptide chemistry, e.g. an acetyl group; the protective group can be released by treating with a weak base.
  • a protective group conventionally used in the field of peptide chemistry, e.g. an acetyl group; the protective group can be released by treating with a weak base.
  • a compound of formula I with a free amino group and/or a free carboxy group can be prepared from a corresponding protected compound by releasing the protective group or groups in conventional manner.
  • a protective group for the amino group such as a trityl or t-butoxycarbonyl group
  • an acid such as trifluoroacetic acid
  • a protective group such as a p-nitrobenzyloxycarbonyl group
  • a protective group for the carboxy group such as a benzhydryl or p-methoxybenzyl group, can be released by an acid and a protective group such as a trimethylsilyl group can be released by the contact with water.
  • the compounds of formula I with a free carboxy group can be converted to pharmaceutically acceptable non-toxic salts thereof in conventional manner.
  • an alkali metal salt of the compound is obtainable by adding to the compound a n-butanol solution of an alkali metal 2-ethylhexanoate and then an organic solvent having a different solubility, such as ether, ethyl acetate, etc.
  • an organic base salt is obtainable by adding thereto an equivalent or slightly excess amount of an organic base such as dicyclohexylamine, triethylamine, diethanolamine, arginine, lysine, etc.
  • an ammonium salt is obtainable by adding aqueous ammonia.
  • the compounds of formula I wherein with a free amino group can also be converted into the pharmaceutically acceptable non-toxic salts thereof in conventional manner, e.g. by adding to the compound an equivalent or slightly excess amount of an inorganic acid such as hydrochloric acid, phosphoric acid, sulfuric acid, etc., or of an organic acid such as fumaric acid, maleic acid, malic acid, citric acid, benzoic acid, etc.
  • an inorganic acid such as hydrochloric acid, phosphoric acid, sulfuric acid, etc.
  • an organic acid such as fumaric acid, maleic acid, malic acid, citric acid, benzoic acid, etc.
  • reaction mixture was added 100 ml of ice-water and after neutralizing it by adding a small amount of hydrochloric acid, the reaction mixture was extracted once each with 50 ml and 30 ml of ethyl acetate.
  • the ethyl acetate extract was washed four times with water and after drying with anhydrous magnesium sulfate, the solvent was distilled off to provide 3.5 g of crude methyl 3-hydroxy-2-(2-tritylaminothiazol-4-yl)propionate.
  • the product was purified by silica gel column chromatography using a mixture of benzene and ethyl acetate in 3:1 by volume ratio as eluent.
  • the powder formed was recovered by filtration and washed with, ether to provide 680 mg of 7 ⁇ -[3-hydroxy-2-(2-tritylaminothiazol-4-yl)propionamido]-3-(1-methyltetrazol-5-yl)thiomethyl- ⁇ 3 -cephem-4-carboxylic acid benzhydryl ester.
  • the powder formed was recovered by filtration and washed with ether to provide 680 mg of 7 ⁇ -[3-hydroxy-2-(2-tritylaminothiazol-4-yl)propionamido]-3-(1-methyltetrazol-5-yl)thiomethyl-A3 - cephem-4-carboxylic acid benzhydryl ester.
  • reaction mixture obtained was dried in a solid under reduced pressure and the residue was washed with isopropyl ether and then purified by column chromatography using Diaion HP 20 (trade name of ionexchange resin, made by Mitsubishi Chemical Industries, Ltd.) to provide 7 ⁇ -[2-(2-aminothiazol-4-yl)-3-hydroxypropionamido]-3-[(1-methyltetrazol-5-yl)thiomethy]- ⁇ 3 -cephem-4-carboxylic acid.
  • Diaion HP 20 trade name of ionexchange resin, made by Mitsubishi Chemical Industries, Ltd.
  • the filtrate was washed twice with water acidified by hydrochloric acid, once with an aqueous solution of sodium hydrogencarbonate, and once with an aqueous solution of sodium chloride. After drying the filtrate by anhydrous magnesium sulfate, the solvent was distilled off and ether was added to the residue to provide 440 mg of 3-acetoxymethyl-7 ⁇ -[3-hydroxy-2-(2-tritylaminothiazol-4-yl)propionamido]-13-cephem-4-carboxylic acid benzhydryl ester.
  • the ester was treated as in Example 2 to release the protective group and purified as in Example 2 to provide 3-acetoxymethyl-7 ⁇ -[2-(2-aminothiazol-4-yl)-3-hydroxypropionamido]- ⁇ 3 -cephem-4-carboxylic acid.
  • the product was dissolved in a mixture of 15 ml of trifluoroacetic acid and 1 ml of anisole followed by stirring for 10 minutes at room temperature. After further adding 10 ml of water to the mixture at temperatures below room temperature, the resultant mixture was stirred for 30 minutes at room temperature.
  • the reaction mixture was concentrated under reduced pressure and ether was added to the residue and the wall of the container was rubbed to form a powder, which was recovered by filtration and washed with ether.
  • the powder was suspended in 10 ml of isopropanol and after adding pyridine to the suspension and adjusting the pH to 4, the mixture was stirred for 30 minutes at room temperature. The powder was then recovered by filtration and washed with isopropanol to provide crude 7 ⁇ -[2-(2-aminothiazol-4-yl)-3-hydroxypropionamido]-3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl- ⁇ 3 -cephem-4-carboxylic acid.
  • the product was purified by column chromatography using Diaion HP 20 (trade name) to provide a pure product.
  • the above mixture was finely pulverized and filled in 1,000 capsules.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Cephalosporin Compounds (AREA)

Claims (8)

1. Ein Cephalosporinderivat der allgemeinen Formel
Figure imgb0054
in der R Wasserstoff oder eine Carbamoylgruppe und R2 eine Acetoxygruppe, eine (1-Methyl-tetrazol-5-yl)thiogruppe oder eine (5-Methyl-1,3,4-thiadiazol-2-yl)thiogruppe bedeutet und gegebenenfalls eine der beiden Aminogruppen oder beide Aminogruppen und die Carbonsäuregruppe geschützt sind.
2. 7β-[2-(2-Aminothiazol-4-yl)-3-hydroxypropionamido]-3-[(1-methyltetrazol-5-yl)thiomethyl]-Δ3-- cephem-4-carbonsäure gemäß Anspruch 1.
3. 3-Acetoxy-7β-[2-(2-aminothiazol-4-yl)-3-hydroxypropionamido]-Δ3-cephem-4-carbonsäure gemäß Anspruch 1.
4. 7β-[2-(2-Aminothiazol-4-yl)-3-hydroxypropionamido]-3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-Δ3-cephem-4-carbonsäure gemäß Anspruch 1.
5. 7,ß-[2-(2-Aminothiazol-4-yl)-3-carbamoyloxypropionamido]-3-(1-methyltetrazol-5-yl)thiomethyl-A3-cephem-4-carbonsäure gemäß Anspruch 1.
6. Ein Salz einer Verbindung nach einem der vorangegangenen Ansprüche.
7. Verfahren zur Herstellung eines Cephalosporinderivats nach Anspruch 1, dadurch gekennzeichnet, daß man (a) ein 7-Aminocephalosporinderivat der allgemeinen Formel
Figure imgb0055
oder ein reaktionsfähiges Derivat davon, dessen Aminogruppe substituiert ist, wobei R2 die gleiche Bedeutung wie in Anspruch 1 hat und die Carboxygruppe durch eine gebräuchliche Schutzgruppe geschützt sein kann, mit (b) einem Thiazolylpropionsäurederivat der allgemeinen Formel
Figure imgb0056
oder einem reaktionsfähigen Derivat davon, in dem die Carbonsäuregruppe substituiert ist, wobei R die gleiche Bedeutung hat wie in Anspruch 1 und die Hydroxygruppe, wenn R für Wasserstoff und/oder die Aminogruppe steht, durch eine übliche Schutzgruppe geschützt sein kann, umsetzt, gegebenenfalls die erhaltene Verbindung behandelt, um etwa vorhandene Schutzgruppen in die freien Gruppen umzuwandeln und gegebenenfalls das Reaktions-produkt in ein Salz davon umwandelt.
8. Arnzneimittel, enthaltend ein Cephalosporinderivat nach einem der Ansprüche 1 bis 6, in einem pharmazeutisch verträglichen Träger.
EP80301917A 1979-06-07 1980-06-06 7-(Thiazolylpropionamido)-cephalosporine, ihre Herstellung und sie enthaltende pharmazeutische Zusammensetzungen Expired EP0021688B1 (de)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
JP71595/79 1979-06-07
JP7159579A JPS55164690A (en) 1979-06-07 1979-06-07 7- 2- 2-aminothiazole-4-yl 3-hydroxypropionamide cephalosporin compound and its preparation
JP30019/80 1980-03-10
JP3001980A JPS56127388A (en) 1980-03-10 1980-03-10 7- 2- 2-aminothiazol-4-yl -3-substituted propionamide - cephalosporin compound, and its preparation

Publications (2)

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EP0021688A1 EP0021688A1 (de) 1981-01-07
EP0021688B1 true EP0021688B1 (de) 1983-07-13

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Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DK154939C (da) * 1974-12-19 1989-06-12 Takeda Chemical Industries Ltd Analogifremgangsmaade til fremstilling af thiazolylacetamido-cephemforbindelser eller farmaceutisk acceptable salte eller estere deraf
GB1575803A (en) * 1976-03-09 1980-10-01 Fujisawa Pharmaceutical Co 3,7 disubstituted 3 cephem 4 carboxylic acid compounds andprocesses for the preparation thereof
US4440766A (en) * 1976-03-09 1984-04-03 Fujisawa Pharmaceutical Co., Ltd. 3,7-Disubstituted-3-cephem-4-carboxylic acid compounds
GR63088B (en) * 1976-04-14 1979-08-09 Takeda Chemical Industries Ltd Preparation process of novel cephalosporins
FI771866A (de) * 1976-06-28 1977-12-29 Fujisawa Pharmaceutical Co
US4370326A (en) * 1977-09-13 1983-01-25 Fujisawa Pharmaceutical Co., Ltd. Cephem compounds and composition

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US4581353A (en) 1986-04-08
DE3064106D1 (en) 1983-08-18

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